# Optimizing PepTAC structure and amphiphilicity for enhanced target protein degradation

> **NIH NIH R01** · CORNELL UNIVERSITY · 2024 · $316,226

## Abstract

Project Summary
This study seeks to advance heterobifunctional degraders that induce targeted protein degradation through
the ubiquitin proteasome pathway. Typically, molecular degraders involve a ligand that recruits an E3
ubiquitin ligase and another that targets a protein of interest (POI), forming an E3:Degrader:POI ternary
complex, leading to POI ubiquitination and subsequent degradation by the 26S proteasome. Peptide-based
proteolysis targeting chimeras (PepTACs) offer distinct advantages over small molecule degraders for
targeting protein-protein interactions due to their specificity, manufacturability, ease of design, and expansive
binding surface area. However, due to challenges related to their limited cellular permeability and stability,
which is evident in the modest potencies (micromolar range) of recently reported PepTACs, structure-function
studies to improve their catalytic activity have not been investigated. We highlight a recent breakthrough
where we facilitate PepTAC transport at nanomolar concentrations into cells via lipid nanoparticles (LNPs),
establishing a robust platform for our proposed studies. We aim to explore the structural attributes of
PepTACs to improve their catalytic activity and enhance target protein degradation. Our hypothesis revolves
around modifying PepTAC structure and amphipathicity to improve degradation efficiency, leveraging prior
literature showing that small molecule degraders with enhanced ternary complex stability drive greater target
protein degradation rates. Our study comprises three key aims: the first focuses on identifying the optimal
location of the E3 ligand to create a PepTAC that promotes enhanced positive cooperativity and rapid
ubiquitination. The second aim investigates how PepTAC structure impacts LNP loading, stability, and
intracellular transport. Finally, our third aim proposes a universal strategy for LNP loading based on tuning
PepTAC lipophilicity to enhance LNP encapsulation and systemic stability. Achieving these aims would
unlock the potential of PepTACs as valuable tools for cell-specific targeted protein degradation and
broadening access to a valuable class of peptide-based protein degraders.

## Key facts

- **NIH application ID:** 10978771
- **Project number:** 1R01GM155900-01
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Christopher Akinleye Alabi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $316,226
- **Award type:** 1
- **Project period:** 2024-07-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978771

## Citation

> US National Institutes of Health, RePORTER application 10978771, Optimizing PepTAC structure and amphiphilicity for enhanced target protein degradation (1R01GM155900-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10978771. Licensed CC0.

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